Preparation of 4-amino-1-naphthol ethers

ABSTRACT

The present invention describes a process for preparing 4-amino-1-naphthol ethers which is characterized in that naphthol ethers are first prepared from 1-naphthols, the former are then converted to the corresponding 4-acetamino-1-naphthol ethers and then the acyl group is cleaved off, and further describes 4-acetamino-1-naphthol ethers obtained thereby.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for preparing4-amino-1-naphthol ethers and novel intermediates.

2. Brief Description of the Prior Art

4-Amino-1-naphthol ethers are valuable intermediates in preparing activepharmaceutical ingredients (see, for example, WO 00/43384; B. Bachman,J. Wetzel, J. Org. Chem., 11, 1946, p. 454-462; R. Herbst, P. Johnson,J. Org. Chem., 17, 1952, p. 693-697). The synthetic route disclosed, forexample, by WO 00/43384 starts from 4-amino-1-naphthol hydrochloride andcomprises the conversion of the amine to a protected derivative, thealkylation of the hydroxy group and then the cleavage of the protectinggroup. This process has the disadvantage that both the reactant and theprotecting group reagents used are very expensive and the conversion tothe desired 4-amino-1-naphthol ethers still requires three steps. Thesynthesis of 4-amino-1-methoxynaphtalene according to B. Bachman, J.Wetzel, J. Org. Chem., 11, 1946, p. 454-462 is similar and accordinglyhas the same disadvantages.

There is accordingly a need to develop an efficient process which,starting from inexpensive 1-naphthols, facilitates the preparation of4-amino-1-naphthol ethers in a few steps.

SUMMARY OF THE INVENTION

A process for preparing 4-amino-1-naphthol ethers has now been foundthat is characterized in that

-   a) substituted or unsubstituted 1-naphthols are reacted with    reactive alkyl compounds optionally in the presence of a base, to    give 1-naphthol ethers,-   b) the 1-naphthol ethers are then converted to the corresponding    4-acylamino-1-naphthol ethers using hydroxylammonium salts and    carboxylic acids and-   c) these 4-acylamino-1-naphthol ethers are converted to the free    4-amino-1-naphthol ethers or analogous ammonium salts by acidic or    basic acyl group cleavage.

DETAILED DESCRIPTION OF THE INVENTION

Preference is given to using the substituted or unsubstituted1-naphthols of the general formula (I) for step a) of the processaccording to the invention

where

-   R² is hydrogen, halogen or C₁-C₄-alkyl and-   R³ is hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy and-   n is zero, one, two, three or four and-   R⁴ are each independently halogen, nitro, cyano, protected formyl,    C₁-C₈-alkyl, C₇-C₁₀-arylalkyl, C₁-C₈-hydroxyalkyl, C₁-C₈-haloalkyl    or C₆-C₁₀-aryl or substituents of the general formula (II),    D-E-F  (II)    -   where, independently,    -   D is absent or is a C₁-C₈-alkylene radical and    -   E is a carbonyl group or sulphonyl group and    -   F is R⁶, OR⁶, NH₂, SR⁶, NHR⁶ or NR⁶R⁷,        where-   R⁶ and R⁷ are each independently substituted or unsubstituted    C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or-   NR⁶R⁷ together is a 5- to 8-membered heterocycle.

Alkyl or alkylene in the context mentioned are each independently astraight-chain, cyclic, branched or unbranched alkyl or alkyleneradical. The same applies to the alkyl moiety of an arylalkyl radical.

Examples of C₁-C₄-alkyl radicals include methyl, ethyl, n-propyl,isopropyl and n-butyl, and for C₁-C₈-alkyl radicals also n-pentyl,n-hexyl, cyclohexyl, n-heptyl, n-octyl and isooctyl.

Examples of C₁-C₈-alkylene radicals include methylene, 1,1-ethylene,1,2-ethylene, 1,2-propylene, 1,3-propylene, 1,4-butylene and1,2-cyclohexylene.

Examples of C₇-C₁₂-arylalkyl radicals include benzyl and p-methylbenzyl.

Examples of C₁-C₄-alkoxy radicals include methoxy, ethoxy, n-propoxy,isopropoxy and n-butoxy.

The term aryl refers both to carbocyclic and heteroaromatic radicals inwhich none, one, two or three skeletal carbon atoms per cycle, but atleast one skeletal carbon atom in the entire radical, is substituted byheteroatoms selected from the group consisting of nitrogen, sulphur andoxygen. The carbocyclic aromatic radicals or heteroaromatic radicals mayfurther be substituted by up to five identical or different substituentsper cycle selected from the group consisting of bromine, chlorine,fluorine, nitro, cyano, free or protected formyl, C₁-C₈-alkyl,C₁-C₈-hydroxyalkyl and radicals as defined for the general formula (II).

Carbocyclic, aromatic radicals or heteroaromatic radicals may be, forexample, substituted or unsubstituted phenyl, pyridyl, imidazolyl orpyrazolyl.

The same applies to the aryl moiety of an arylalkyl radical.

Halogen in the context mentioned is fluorine, chlorine, bromine oriodine.

Haloalkyl in the context mentioned is independently a straight-chain,cyclic, branched or unbranched alkyl radical which is substituted byone, more than one or completely by halogen atoms selected independentlyfrom the group consisting of fluorine, chlorine and bromine.

Examples of C₁-C₈-haloalkyl radicals include trifluoromethyl,pentafluoroethyl, 2,2,2-trifluoroethyl, trichloromethyl and2-chloroethyl.

Each hydroxyalkyl in the context mentioned is independently astraight-chain, cyclic, branched or unbranched alkyl radical which issubstituted by one or more hydroxyl groups in such a way that eachcarbon atom of the radical bears not more than one oxygen, sulphur ornitrogen atom.

Examples of C₁-C₈-hydroxyalkyl radicals include hydroxymethyl and2-hydroxyethyl.

Protected formyl is a formyl radical which is protected by conversion toaminal, acetal or a mixed aminalacetal, and the aminals, acetals andmixed aminalacetals may be acyclic or cyclic.

A 5- to 8-membered heterocycle is a heterocycle which, as well as anitrogen, also contains up to 3 further heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulphur.

Examples of such heterocycles include unsubstituted or substitutedpyrrolidines, piperidines or morpholines.

Particular preference is given to using substituted or unsubstituted1-naphthols of the general formula (I) in step a) of the processaccording to the invention where

-   R² is hydrogen and-   R³ is hydrogen and-   n is zero, one or two and-   R⁴ are each independently halogen, nitro, cyano, C₁-C₈-alkyl,    C₁-C₈-haloalkyl or substituents of the general formula (III),    where, independently,    -   D is absent and    -   E is a carbonyl group or sulphonyl group and    -   F is R⁶, OR⁶, NH₂, NHR⁶ or NR⁶R⁷ and where-   R⁶ and R⁷ are each independently substituted or unsubstituted    C₁-C₄-alkyl.

Very particular preference is given to using 1-naphthol in step a).

The substituted or unsubstituted 1-naphthols are reacted in step a) withreactive alkyl compounds to give 1-naphthol ethers, optionally in thepresence of a base.

Examples of reactive alkyl compounds include compounds of the generalformula (IIIa) or (IIIb),R¹—Y  (IIIa)(R¹—O)₂SO₂  (IIIb)where, for example,

-   R¹ is C₃-C₁₂-alkyl, C₂-C₈-haloalkyl, C₇-C₁₃-arylalkyl or    substituents of the general formula (IV),    A-B  (IV)    -   where    -   A is C₂-C₈-alkylene, C₂-C₈-haloalkylene and    -   B is NR⁶R⁷, SR⁶ or OR⁶        where-   R⁶ and R⁷ are each independently substituted or unsubstituted    C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or-   NR⁶R⁷ together is a 5- to 8-membered heterocycle and-   Y is chlorine, bromine, iodine or sulphonate.    Particular preference is given to using activated alkyl compounds of    the general formula (IIIa) where-   R¹ is a substituent of the general formula (IV) where-   A is C₂-C₄-alkylene or C₂-C₄-haloalkylene and-   B is NR⁶R⁷ or OR⁶ and    where-   R⁶ and R⁷ are each independently substituted or unsubstituted    C₁-C₄-alkyl or-   NR⁶R⁷ together is a 5- or 6-membered heterocycle and-   Y is chlorine, bromine, iodine, methanesulphonate, tosylate or    trifluoromethanesulphonate.

Very particular preference is given to using activated alkyl compoundsof the general formula (IIIa) where

-   R¹ is a substituent of the general formula (IV) where-   A is 1,2-ethylene and-   B is NR⁶R⁷ or OR⁶,    where-   R⁶ and R⁷ are each independently substituted or unsubstituted    C₁-C₄-alkyl or-   NR⁶R⁷ together is pyrrolidinyl, piperidinyl or morpholinyl and-   Y is chlorine, bromine or trifluoromethanesulphonate.

Greatest preference is given to N-(2-chloroethyl)morpholine,N-(2-bromoethyl)morpholine, N-(2-methanesulphonylethyl)morpholine, andeven greater preference to N-(2-chloroethyl)morpholine.

Preference is given to using the compounds of the general formulae(IIIa) and (IIIb) when they contain an amine nitrogen in the form oftheir ammonium salts.

For example, N-(2-chloroethyl)morpholine is preferably used in the formof a hydrochloride.

The compounds of the general formulae (IIIa) or (IIIb) may be used, forexample, in a molar ratio of from 0.8 to 2.0, based on the substitutedor unsubstituted 1-naphthol used, and preference is given to a ratio offrom 0.9 to 1.5, even greater preference to a ratio of from 1.0 to 1.4.

The conversion of substituted or unsubstituted 1-naphthols to the1-naphthol ethers may be carried out, for example, in the presence ofbase in a suitable solvent at a suitable temperature.

Examples of useful bases include hydroxides, alkoxides, hydrides,amides, carbonates and hydrogen carbonates of alkali metals or alkalineearth metals or amines.

Preference is given to the hydroxides or carbonates of the alkalimetals, more preference to sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate. Very particular preference is given tosodium hydroxide.

Preference is given to using alkali metal hydroxides in the form of anaqueous solution having a base content of from 30 to 70% by weight,greater preference to a solution of from 30 to 70% by weight of sodiumhydroxide in water.

The base quantity may be, for example, from 0.8 to 5.0 equivalents,based on the substituted or unsubstituted 1-naphthol used, preference isgiven to from 0.9 to 1.5 equivalents, even greater preference to from0.9 to 1.2 equivalents.

When, for example, compounds of the general formulae (IIIa) or (IIIb)having amine nitrogen are used in the form of their ammonium salts, thebase quantity has to be increased by a corresponding molar quantity.

Examples of useful solvents for step a) of the process according to theinvention include aliphatic or aromatic hydrocarbons, such as, toluene,xylene or hexane, chlorinated hydrocarbons, such as, chlorobenzene ormethylene chloride, ethers, such as, tetrahydrofuran or diethyl ether,alcohols, such as, methanol, ethanol or isopropanol, esters, such asethyl acetate, or polar aprotic solvents, such as, dimethylformamide ordimethyl sulphoxide, or mixtures of such solvents. Preference is givento carrying out the reaction in an alcohol.

A very particularly preferred solvent for step a) is ethanol.

The temperature for step a) may, for example, be from 0 to 120° C.,preferably from 20 to 80° C., more preferably from 40 to 80° C.

The pressure during the reaction is preferably ambient pressure.

In a preferred embodiment of step a), for example, the substituted orunsubstituted 1-naphthol and the reactive alkyl compound, for exampleN-(2-chloroethyl)morpholinyl hydrochloride, is initially charged inethanol and sodium hydroxide is added as a 30-70% aqueous solution atfrom 40 to 60° C.

In the manner according to the invention, 1-naphthol ethers, forexample, of the general formula (V) are obtained,

where

-   R¹, R², R³, R⁴ and n are as defined above with the areas of    preference mentioned.

The acylamination of the electron-rich aromatics, for example a1-methoxynaphtalene, is disclosed by T. Cablewski et al., J. Org. Chem.,1994, 59, p. 5814-5817, but the process described there is only slightlyregioselective.

According to the invention, step b), the conversion of the 1-naphtholethers to 4-acylamino-1-naphthol ethers may, for example, be carried outin such a way,

that the 1-naphthol ethers are reacted with a hydroxylammonium salt anda carboxylic acid in the presence of polyphosphoric acid.

For the purposes of the present invention, polyphosphoric acid refers tosuch polyphosphoric acids which have a content of over 100%, based onorthophosphoric acid.

Preference is given to a content of from 100% to 300%, more preferablyfrom 100% to 150%. Very particular preference is given to commercialpolyphosphoric acid having a content of 116%, based on orthophosphoricacid.

The quantity of the polyphosphoric acid used may, for example, be from 5to 12 times, preferably from 5 to 8 times, the molar quantity of theunsubstituted or substituted 1-naphthol ether. The molar quantity ofpolyphosphoric acid reported is based on the content of orthophosphoricacid.

Examples of useful hydroxylammonium salts include hydroxylaminehydrochloride, hydroxylamine hydrogensulphate and hydroxylaminedihydrogenphosphate. Preference is given to hydroxylamine hydrochloride.

Examples of useful carboxylic acids include those of the general formula(VI)

where

-   R⁵ is C₁-C₆-alkyl or C₁-C₄-haloalkyl or anhydrides thereof.

Preference is given to acetic acid, trifluoroacetic acid, propionic acidand anhydrides thereof, and particular preference is given to aceticacid, propionic acid and trifluoroacetic acid. Even greater preferenceis given to acetic acid.

The quantity of the carboxylic acid of the general formula (VI) usedmay, for example, be from 0.8 to 20 times the molar quantity of theunsubstituted or substituted 1-naphthol ether used, preferably from 1.0to 3.0 times, more preferably from 1.2 to 1.5 times.

The temperature during the reaction may, for example, be from 50 to 130°C., preferably from 70 to 120° C.

The overall reaction duration may, for example, be from 1 to 48 hours,preferably from 2 to 10 hours, more preferably from 5 to 8 hours.

In a preferred embodiment of step b), carboxylic acid, hydroxylammoniumsalt and polyphosphoric acid are initially charged and the 1-naphtholether is metered in at a temperature of from 70 to 90° C. over a periodof from 0.5 to 8 hours, preferably from 1 to 5 hours and more preferablyfrom 2 to 4 hours, and then heated at 100-120° C. for a period of from 1to 10 hours, preferably from 1 to 4 hours.

Preference is given to effecting the workup in such a way that thereaction mixture is brought into contact with ice and, optionally afteraddition of water, the pH is adjusted using a base, preferably sodiumhydroxide, to from 9 to 10. Preference is given to holding thetemperature below 40° C., more preferably at or below 25° C.

In the manner according to the invention, for example,4-acylamino-1-naphthol ethers of the general formula (VIIa) areobtained,

where

-   R¹ is C₃-C₁₂-alkyl, C₂-C₈-haloalkyl, C₇-C₁₃-arylalkyl or    substituents of the general formula (IV),    A-B  (IV)    -   where    -   A is C₂-C₈-alkylene, C₂-C₈-haloalkylene and    -   B is NR⁶R⁷, SR⁶ or OR⁶,        where-   R⁶ and R⁷ are each independently substituted or unsubstituted    C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or-   NR⁶R⁷ together is a 5- to 8-membered heterocycle and-   R² is hydrogen, halogen or C₁-C₄-alkyl and-   R³ is hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy and-   n is zero, one, two, three or four and-   R⁴ are each independently halogen, nitro, cyano, protected formyl,    C₁-C₈-alkyl, C₇-C₁₀-arylalkyl, C₁-C₈-hydroxyalkyl, C₁-C₈-haloalkyl    or C₆-C₁₀-aryl or substituents of the general formula (II)    D-E-F  (II)    -   where, independently,    -   D is absent or is a C₁-C₈-alkylene radical and    -   E is a carbonyl group or sulphonyl group and    -   F is R⁶, OR⁶, NH₂, SR⁶, NHR⁶ or NR⁶R⁷,        and where-   R⁶ and R⁷ are each independently substituted or unsubstituted    C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or-   NR⁶R⁷ together is a 5- to 8-membered heterocycle and-   R⁵ is C₁-C₆-alkyl or C₁-C₄-haloalkyl.

The compounds of the general formula (VIIa) are likewise part of thesubject-matter of the invention. Examples of individual compoundsinclude 4-(2-([1]-naphthyloxy-[4]-acetamino)ethyl)morpholine,4-(2-([1]-naphthyloxy-[4]-propionylamino)ethyl)morpholine and4-(2-([1]-naphthyloxy-[4]-trifluoroacetamino)ethyl)morpholine.

The compounds of the general formula (VIIa) may either be stored orreacted further. Preference is given to further reactions. If thecompounds of the general formula (VIIa) are to be stored and R¹ alsocontains amine nitrogen, the compounds can also be converted to theanalogous ammonium compounds. For example,4-(2-([1]-naphthyloxy-[4]-acetamino)ethyl)morpholine,4-(2-([1]-naphthyloxy-[4]-propionylamino)ethyl)morpholine and4-(2-([1]-naphthyloxy-[4]-trifluoro-acetamino)ethyl)morpholine can beconverted to the corresponding morpholinium salts by reacting thecompounds, optionally in a solvent, with an equivalent of an acid, H-An.

The compounds of the general formula (VIIb) accordingly also form partof the subject-matter of the invention

where

-   R⁵ is a C₁-C₆-alkyl or C₁-C₄-haloalkyl radical-   and An⁻    is the anion of an acid.

Preferred H-An acids include mineral acids, for example, sulphuric acid,hydrochloric acid, hydrobromic acid, phosphoric acid or tetrafluoroboricacid, hydrogen halides, for example, hydrogen chloride or hydrogenbromide, carboxylic acids such as those of the general formula (VI),where R⁵ is as defined above, or sulphonic acids, for examplemethanesulphonic acid. The anions, An derive correspondingly from theH-An acids.

The 4-acylamino-1-naphthol ethers may be converted to the corresponding4-amino-1-naphthol ethers according to step c). This step may beeffected in a manner similar to the literature (for example, B. Bachman,J. Wetzel, J. Org. Chem., 11, 1946, p. 454-462), for example, by acidicor alkaline acyl group cleavage, and preference is given to hydrolysisused in an acid, which converts the 4-amino-1-naphthol ethers to theform of ammonium salts. When R¹ radicals which contain amine nitrogenare used, the 4-amino-1-naphthol ether occur in the form of thediammonium salts.

Examples of useful acids include those which have a pKa of 2 or less.Examples thereof include hydrogen halides such as hydrogen chloride,hydrogen bromide or hydrogen iodide, mineral acids, for example,hydrochloric acid, hydrobromic acid, sulphuric and/or phosphoric acid,or organic sulphonic acids, such as methanesulphonic acid, or mixturesof such acids.

Preference is given to hydrochloric acid and sulphuric acid, veryparticular preference to concentrated hydrochloric acid.

In the manner according to the invention, step c) gives4-amino-1-naphthol ethers of the general formula (VIIIa) or the ammoniumsalts thereof of the general formula (VIIIb)

where

-   R¹, R², R³, R⁴ and n are as defined for formula (VIIa) and-   X is the anion of an acid.    If the R¹ radical contains amine nitrogen, the formula (VIIIb) also    includes the ammonium salts thereof.

An example of an individual compound is4-(2-([1]-naphthyloxy-[4]-amino)ethyl)morpholine dihydrochloride.

The compounds of the general formulae (VIIa), (VIIb), (VIIIa) and(VIIIb) are suitable in particular for use in a process for preparingpharmaceuticals.

The process according to the invention is in particular notable in thatit uses the inexpensive 1-naphthols as starting substances and leadsselectively in a few steps to the desired 4-amino-1-naphthol ethers orammonium salts thereof in high yields.

The invention is further illustrated but is not intended to be limitedby the following examples in which all parts and percentages are byweight unless otherwise specified.

EXAMPLES Example 1 Preparation of 4-(2-([1]-naphthyloxy)ethyl)morpholine

441 g of 1-naphthol and 648 g of N-(2-chloroethyl)morpholinehydrochloride are initially charged in 2680 ml of ethanol at 50° C. 554g of 50% aqueous sodium hydroxide are added dropwise within 3 h.Stirring is then continued at 50° C. for 3 h and then for 1 h underreflux.

The salt formed is filtered off and washed with ethanol. The combinedfiltrates are concentrated on a rotary evaporator “to dryness” at 80° C.in a bath and 10 mbar. The cooled residue is dissolved in 1200 ml ofdiethyl ether and extracted first with 180 ml of water, then twice with450 ml of 5% aqueous sodium hydroxide each time and finally twice with150 ml of water each time. The ether phase is dried over sodium sulphateand concentrated at 60° C. and 10 mbar to dryness.

Yield: 741 g 4-(2-([1]-naphthyloxy)ethyl)morpholine in a purity of 97.7%(GC). This corresponds to 93.8% of theory, based on 1-naphthol.

Example 2 Preparation of4-(2-([1]-naphthyloxy-[4]-acetamido)ethyl)morpholine

376 g of glacial acid and 224 g of hydroxylammonium chloride areinitially charged in 2090 g of polyphosphoric acid at 80° C. in astirred flask. 830 g of 4-(2-([1]-naphthyloxy)ethyl)morpholine aremetered in with good stirring within 3 h. During the metering in, thetemperature should not exceed 90° C. Stirring is then continued first at80-90° C. for 1 h and then at 115° C. for a further 3 h.

The reaction mixture is allowed to cool to 80° C. and stirred with 1800g of ice. The temperature is allowed to fall to 30-35° C. After additionof 9.75 l of water, precipitation is effected using 50% aqueous sodiumhydroxide (2005 g) to a pH of 4-5. During the precipitation, thetemperature should not exceed 25° C. Stirring is continued for 30 minand the precipitate is then filtered off. The resulting filtercake iswashed with a little water.

The filtercake is suspended in 10 l of water and is dissolved withheating to 90° C. The solution is clarified using activated carbon. 530g of 50% aqueous sodium hydroxide is added with stirring in 1 h until apH of is obtained. The resulting crystal suspension is filtered off at50° C. and the resulting filtercake washed to neutrality with a lot ofwater. The filtercake is then dried in a vacuum drying cabinet.

Weight: 846 g of 4-(2-([1]-naphthyloxy-[4]-acetamido)ethyl)morpholine ina purity of 99.3% (HPLC). This corresponds to 85.1% of theory, reckonedon 4-(2-([1]-naphthyloxy)ethyl)morpholine

Elemental analysis:

Theoretical: C=68.77% H=7.05% N=8.91% Found: C=68.65% H=6.9% N=8.8%

Example 3 4-(2-([1]-Naphthyloxy-[4]-amino)ethyl)morpholinedihydrochloride

846 g of 4-[2-([1]-naphthyloxy-[4]-acetamido)ethyl]morpholine aresuspended in 1340 ml of water and stirred with 2470 g of 37%hydrochloric acid. Hydrolysis is then effected at 95° C. for 5 h. At theend of the reaction time, 1600 g of isopropanol are added and thesuspension is cooled with stirring. The resulting crystals are filteredoff and washed with 4530 g of isopropanol until the filtrate issubstantially colourless. Recrystallization is then effected fromethanol and the product dried in a vacuum drying cabinet.

Yield: 839 g of 4-(2-([1]-naphthyloxy-[4]-amino)ethyl)morpholinedihydrochloride.

Example 4 Preparation of the free4-(2-([1]-naphthyloxy-[4]-amino)ethyl)morpholine

839 g of the dihydrochloride from Example 3 are dissolved in 5600 ml ofwater. In a beaker, 450 ml of water are adjusted to pH 12 using 50%aqueous sodium hydroxide. After seed crystals are created in the aqueoussodium hydroxide initial charge, 50% aqueous sodium hydroxide issimultaneously added dropwise to the remaining solution in such a waythat the pH of 10-12 is maintained. 390 g of 50% aqueous sodiumhydroxide are used. The resulting crystals are filtered off and washedwith 3300 ml of water until the filtrate has a pH of 8. The filtercakeis then dried in the vacuum drying cabinet.

The yield of free amine is virtually quantitative (620 g) in a purity of99.4% (HPLC).

Although the invention has been described in detail in the foregoing forthe purpose of illustration, it is to be understood that such detail issolely for that purpose and that variations can be made therein by thoseskilled in the art without departing from the spirit and scope of theinvention except as it may be limited by the claims.

1. Process for preparing 4-amino-1-naphthol ethers, comprising reacting:a) substituted or unsubstituted 1-naphthols with reactive alkylcompounds to give 1-naphthol ethers, b) converting the 1-naphthol ethersto the corresponding 4-acylamino-1-naphthol ethers usinghydroxylammonium salts and carboxylic acids and c) converting the4-acylamino-1-naphthol ethers to the free 4-amino-1-naphthol ethers oranalogous ammonium salts by acidic or basic acyl group cleavage. 2.Process according to claim 1, wherein the substituted or unsubstituted1-naphthols have the general formula (I)

where R² is hydrogen, halogen or C₁-C₄-alkyl and R³ is hydrogen,halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy and n is zero, one, two, three orfour and R⁴ are each independently halogen, nitro, cyano, protectedformyl, C₁-C₈-alkyl, C₇-C₁₀-arylalkyl, C₁-C₈-hydroxyalkyl,C₁-C₈-haloalkyl or C₆-C₁₀-aryl or substituents of the general formula(II),D-E-F  (II) where, independently, D is absent or is a C₁-C₈-alkyleneradical and E is a carbonyl group or sulphonyl group and F is R⁶, OR⁶,NH₂, SR⁶, NHR⁶ or NR⁶R⁷, and where R⁶ and R⁷ are each independentlysubstituted or unsubstituted C₁-C₈-alkyl, C₁-C₈-haloalkyl,C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or NR⁶R⁷ together is a 5- to 8-memberedheterocycle.
 3. Process according to claim 1 wherein the substituted orunsubstituted 1-naphthols have the general formula (I) where R² ishydrogen and R³ is hydrogen and n is zero, one or two and R⁴ are eachindependently halogen, nitro, cyano, C₁-C₈-alkyl, C₁-C₈-haloalkyl orsubstituents of the general formula (II), where, independently, D isabsent and E is a carbonyl group or sulphonyl group and F is R⁶, OR⁶,NH₂, NHR⁶ or NR⁶R⁷ and where R⁶ and R⁷ are each independentlysubstituted or unsubstituted C₁-C₄-alkyl.
 4. Process according to claim1 wherein the substituted or unsubstituted 1-naphthols is 1-naphthol 5.Process according to claim 1 wherein the reactive alkyl compounds is ofthe general formula (IIIa) or (IIIb) represented byR¹—Y  (IIIa), or(R¹—O)₂SO₂  (IIIb) where R¹ is C₃-C₁₂-alkyl, C₂-C₈-haloalkyl,C₇-C₁₃-arylalkyl or substituents of the general formula (IV),A-B  (IV) where A is C₂-C₈-alkylene, C₂-C₈-haloalkylene and B is NR⁶R⁷,SR⁶ or OR⁶ where R⁶ and R⁷ are each independently substituted orunsubstituted C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl orC₆-C₁₀-aryl or NR⁶R⁷ together is a 5- to 8-membered heterocycle and Y ischlorine, bromine, iodine or sulphonate.
 6. Process according to claim 1wherein the reactive alkyl compounds are of the general formula (IIIa)where R¹ is a substituent of the general formula (IV) where A isC₂-C₄-alkylene or C₂-C₄-haloalkylene and B is NR⁶R⁷ or OR⁶ and where R⁶and R⁷ are each independently substituted or unsubstituted C₁-C₄-alkylor NR⁶R⁷ together is a 5- or 6-membered heterocycle and Y is chlorine,bromine, iodine, methanesulphonate, tosylate ortrifluoromethanesulphonate.
 7. Process according to claim 1 wherein thereactive alkyl compound is 2-(N-morpholinyl)ethyl chloride,2-(N-morpholinyl)ethyl bromide or2-(N-morpholinyl)ethylmethanesulphonate, or ammonium salts thereof. 8.Process according to claim 7 wherein the reactive alkyl compound isN-(2-chloroethyl)morpholine hydrochloride.
 9. Process according to claim1 wherein step a) is effected in the presence of a base.
 10. Processaccording claim 9 wherein step a) is effected in the presence of anaqueous solution of sodium hydroxide having a concentration of from 30to 70% by weight.
 11. Process according to claim 1 wherein step a) iscarried out in ethanol.
 12. Process according to claim 1 wherein step a)is carried out at a temperature of from 0 to 120° C.
 13. Processaccording to claim 1 wherein step b) is carried out in the presence ofpolyphosphoric acid.
 14. Process according to claim 13 wherein the molarratio of polyphosphoric acid to 1-naphthol ether is from 5.0 to 12.0.15. Process according to claim 1 wherein the hydroxylammonium salt ishydroxylamine hydrochloride.
 16. Process according to claim 1 whereinthe carboxylic acid is acetic acid, propionic acid or trifluoroaceticacid.
 17. Process according to claim 1 wherein the reaction temperaturein step b) is from 50 to 130° C.
 18. Process according to claim 1wherein the 4-acylamino-1-naphthol ethers are converted by acidhydrolysis to the ammonium salts of 4-amino-1-naphthol ethers in stepc).
 19. Process according to claim 18 wherein the acid hydrolysis iscarried out in the presence of acids having a pKa of 2 or less in stepc).
 20. Process according to claim 19 wherein the acid hydrolysis iscarried out in the presence of concentrated hydrochloric acid. 21-25.(canceled)
 26. Compounds of the general formulae (VIIIa) and (VIIIb),

where R¹, R², R³, R⁴ and n are as defined under formula (VII) and X isthe anion of an acid.
 27. The compound of formula (VIIIa) or (VIIIb)which is 4-(2-([1]-napthyloxy-[4]-amino)ethyl)morpholine dihydrochlorideor the ammonium salt thereof.
 28. A process for preparing pharmaceuticalcompounds comprising providing compounds of the general formulae (VIIIa)and (VIIIb),

where R¹, R², R³, R⁴ and n are as defined under formula (VII) and X isthe anion of an acid.